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Principal Investigator: Gabriel D Victora
Organization: ROCKEFELLER UNIVERSITY
Fiscal Year: 2023
Award: $628,260
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Generating an appropriate antibody response is critical for protection against reinfection and for the effectiveness
of vaccination, particularly in the context of viral diseases. In addition to well-studied quantitative parameters
such as antibody titer and affinity, other, more qualitative parameters related to the clonal composition of the
response also play critical roles in antibody-mediated protection. These include antigen and epitope specificity,
which is key to viral neutralization capacity and antibody breadth, and overall clonal diversity, which strongly
influences the degree of immunodominance and therefore the ability of viruses to escape immunity by mutation.
Despite their importance, such “ecological” aspects of GC biology remain poorly understood and systematically
understudied at the mechanistic level.
Our long-term goal is to develop a mechanistic understanding of how the competitive waxing and waning of B
cell clones at the various stages of the immune response shapes the ultimate composition, specificity, and
protective efficacy of serum antibody. In our previous studies, using multicolor “Brainbow”-based B cell fate-
mapping models, we focused on the germinal center (GC) and memory phases of the response, revealing how
highly diverse early responders are funneled towards oligoclonality, first progressively by GC selection (including
in chronic gut-associated GC) and then dramatically by secondary boosting. We now propose to extend our work
using these same tools to investigate the clonal dynamics of prolonged selection in long-lived virus-induced GCs
(Aim 1) and of the progressive differentiation of plasmablasts and plasma cells from GC precursors (Aim 2). We
also propose a new “molecular fate-mapping” system to determine how clonal dynamics impact the ultimate
composition of serum antibody (Aim 3). This allows us to investigate the B cell biology of serum-level phenomena
such as antigenic imprinting/original antigenic sin, immunodominance, and viral escape.
We expect our findings will provide greater mechanistic understanding of how the composition and protective
effectiveness of serum antibody is determined by the dynamics of B cell clonal competition, with implications for
the design of effective vaccination strategies for influenza, HIV, and SARS-CoV-2.
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